Multiple myeloma evolves from the premalignant condition, monoclonal gammopathy of undetermined significance (MGUS). This project has defined the prevalence of MGUS, the risk of progression of MGUS to MM, risk factors for progression, and association of MGUS with other diseases. Since MM is incurable, it is imperative to understand and characterize its premalignant stages so interventions that prevent or delay progression of MGUS to MM are possible. To achieve this goal, we identified 4 crucial questions that must be addressed: 1) what are the additional predictors of progression that can define a subset of MGUS patients with a risk of progression high enough to warrant intervention? (MGUS has a 1% per year risk of progression. In the preceding funding period we identified risk factors that increase this risk to 3-4% per year. With studies proposed in this grant, our goal is to identify a high-risk group with a 10% risk of progression per year); 2) what is the premalignant stage responsible for up to 20% of MM (light chain MM) that is not preceded by MGUS?; 3) what role do genetic or familial factors play in MGUS? and 4) what is the natural history of smoldering multiple myeloma? Our Specific Aims correspond to these 4 key questions. In Aim 1, we will test the predictive value of 4 key factors chosen based on specific hypotheses, understanding of MGUS biology, and preliminary data. They are monoclonal serum free light chains, circulating plasma cells, microvessel density, and angiogenic ability of marrow plasma. In Aim 2, we will study the precursor lesion for 20% of MM (light chain MM) that is not preceded by typical MGUS. We hypothesize and have preliminary data for the presence of a new entity called "light chain MGUS" that leads to light chain MM. We will study the prevalence, risk of progression, and predictors of progression and survival of light chain MGUS in a population-based study using serum samples from over 21,000 residents of OImsted County. In Aim 3, we will study the prevalence of MGUS in first-degree relatives of Olmsted County residents with known MGUS. We have preliminary data that there is familial clustering of MGUS, and familial incidence of MM has been reported. Families in which 3 or more first degree relatives are affected with MGUS will be candidates for collaborative studies to look for genetic polymorphisms that predispose to MGUS. Finally, in Aim 4, we will study the progression rate and prognostic factors for smoldering myeloma, a post-MGUS disease stage with a high risk of progression to MM.